Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne disease in the United States. Among the symptoms occurring as a result of infection with B. burgdorferi, Lyme arthritis is the most prevalent in patients infected with the spirochete. B. burgdorferi infection causes an upregulation of proinflammatory cytokines. Tumor necrosis factor (TNF) alpha, IL-12 and Interferon (IFN) gamma, followed by a CD4+ T cell helper (Th) type 1 cytokine production pattern have been reported in strains susceptible to develop more severe inflammatory symptoms. The molecular mechanisms by which the proinflammatory cytokine pattern is induced are not completely elucidated. p38 MAP kinase is involved in the genesis of several non-infectious arthritides, like rheumatoid arthritis, by regulating the expression of proinflammatory cytokines, p38 MAP kinase is also required for the production of IFNgamma, an important proinflammatory mediator, by T cells. The use of a specific inhibitor is considered a potential therapy in those processes that involve a proinflammatory response mediated by p38 MAP kinase. We hypothesize that B. burgdorferi activates the p38 MAP kinase pathway. The activation of this pathway is required for proinflammatory cytokine production by macrophages and neutrophils. The activation of this pathway is also required for IFNgamma production by CD4+ T cells and Thl differentiation during Lyme borreliosis. Thus, we propose that the p38 MAP kinase pathway is required for the development of murine Lyme arthritis. Understanding the contribution of this pathway to the development of murine Lyme arthritis, as a model of human disease, may open new therapeutic approaches that would take advantage of specific pharmacological inhibitors of p38 MAP kinase currently being tested in human clinical trials.